Project Summary Despite the availability of evidence-based strategies such as high-dose statins, cardiovascular disease (CVD) remains the leading cause of death worldwide. Statins effectively reduce plasma low-density lipoprotein cholesterol (LDL-C) concentrations and prevent cardiovascular events; however, there is a great deal of variability and inadequate response to statins. Additionally, susceptible individuals continue to experience cardiac events even while on aggressive statin therapy, referred to as residual risk. Therefore we need to improve our understanding of the factors contributing to pharmacological variability to statin therapy. Understanding the variability in pharmacologic treatment and the best strategy for addressing residual risk will enhance our efforts in decreasing CVD related morbidity and mortality. Accumulating evidence suggests that intestinal microbiota impacts the development of CVD, host plasma lipid levels, metabolism of xenobiotics, and has shown to be a contributing factor in drug variability. Importantly, is unknown whether the gut microbiome impacts the efficacy of statin medications. The objective of this proposal is to understand the interaction between the gut microbiome and host drug response to statin therapy using 16S rRNA sequencing, metagenomics sequencing and bile acid metabolomics, as well as provide the applicant with a patient-oriented mentored training program to gain expertise in metagenomics and metabolomic data interpretation and analysis. In Aim 1, a placebo-controlled interventional study will be performed in 90 healthy subjects to determine if rosuvastatin impacts the gut microbiota composition. Stool samples at before and after treatment will be analyzed by 16S rRNA and metagenomics sequencing. In Aim 2, the contribution of gut-derived bile acid metabolites and fibroblast growth factor (FGF)-19 to the LDL-C lowering effect of rosuvastatin will be determined. Stool samples will be analyzed by targeted metabolomic analysis. A career development and training plan for the applicant is outlined including training in metagenomics and metabolomics methodology required for completion of this project. The University of Pennsylvania is a world-class research institute and a wonderful environment for this training and research. This proposal is innovative and unique in that it integrates human models of drug-induced metagenomics and metabolomic signatures with drug response. A better understanding of the complex interactions of the gut microbiome with host drug response to statin therapy could advance our understanding of additional factors contributing to the variability of drug response, identify poor responders to treatment and inform the development of novel therapeutics for targeting residual risk in CVD. Most importantly, this research and training will provide the applicant with the means to discover clinically relevant drug response biomarkers and drug targets that will improve outcomes for patients with CVD.